TO THE EDITOR
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the most common etiology of chronic liver disease worldwide[1,2]. Its prevalence varies geographically, with recent estimates indicating a global rate of approximately 25%[3]. A substantial body of evidence indicates that this burden has increased over the past two to three decades, a trend projected to persist in parallel with the global obesity epidemic[4]. Moreover, accumulating data demonstrate that the consequences of MASLD extend beyond hepatic complications, manifesting significant extrahepatic associations, most notably with cardiovascular disease (CVD)[5]. CVD is now recognized as a critical comorbidity that influences the clinical trajectory of MASLD, ranking second only to cirrhosis as a potential cause of death, while simultaneously constituting the most frequent direct cause of mortality in this patient population[6]. Within this context, the study by Mapouka et al[7], published in the World Journal of Gastroenterology and entitled "Outcomes of liver and cardiovascular metabolic diseases among lean vs non-lean individuals with metabolic dysfunction-associated steatotic liver disease", is of considerable relevance.
Mapouka et al[7] conducted a meta-analysis spanning 20 years of data from multiple databases, encompassing 10735550 individuals with MASLD. The authors assessed seven clinical outcomes—liver fibrosis, steatosis, metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, CVD, hypertension, and all-cause mortality—comparing cohorts with normal body mass index (BMI) to those with obesity.
Overall, the investigation by Mapouka et al[7] is of considerable relevance; however, several limitations merit attention. First, this meta-analysis was based on secondary data. Published studies on MASLD and CVD were selected for statistical synthesis, yet many of the constituent articles employed disparate criteria for defining obesity, thereby introducing a degree of bias. Second, the inclusion of both European and Asian cohorts—populations in whom BMI thresholds differ—undoubtedly contributed to the substantial heterogeneity observed. The authors themselves acknowledge this for outcomes such as mortality (I2 = 90.9%), MASH (I2 = 91%), and fibrosis (I2 = 94%). The marked inconsistency across these endpoints necessitates cautious interpretation of the pooled estimates and underscores the need for standardized definitions of the lean MASLD phenotype in future research.
MASLD is now recognized as an independent risk factor for CVD[8]. Evidence from numerous clinical studies demonstrates that, in this patient population, mortality is more frequently attributable to cardiovascular events than to hepatic complications[9-11]. Furthermore, this condition has been linked to a heightened incidence of atherosclerosis[12], hypertension, valvular heart disease, cardiomyopathy, and arrhythmias[13]. The association between MASLD and cardiovascular pathology is pathophysiologically plausible, as the hallmark features of this hepatic disorder—intrahepatic lipid accumulation, hyperlipidemia, and diabetes—are themselves key determinants of cardiovascular morbidity.
The investigation by Mapouka et al[7] addresses a pressing clinical issue: The interplay between MASLD and CVD in patients with a normal BMI. Within the spectrum of metabolically linked disorders, the key unifying factor for these two conditions in normal-weight individuals is the "metabolically obese normal weight" phenotype[14,15]. The Mapouka et al’s findings[7] corroborate this paradigm by demonstrating comparable odds of CVD between lean and non-lean patients with MASLD (pOR = 0.9, 95%CI: 0.7-1.0, P = 0.1). This observation implies that, at the population level, incident cardiovascular events in MASLD are driven by metabolic dysregulation rather than by adiposity as defined by BMI.
The scientific rationale for this association includes the following pathogenetic mechanisms.
Visceral obesity and ectopic lipid accumulation. In normal-BMI patients with MASLD and CVD, excessive accumulation of visceral adipose tissue and, critically, ectopic lipid deposition in non-adipocyte tissues—hepatocytes (hepatic steatosis) and the myocardium/vascular wall—is frequently observed. This process drives lipotoxicity. MASLD inherently accompanies an expansion of epicardial adipose tissue, and greater epicardial fat thickness correlates with more severe hepatic fibrosis[16]. Located in close proximity to the coronary arteries and myocardium, this visceral fat depot shares a common microcirculation with the underlying cardiac muscle and secretes pro-inflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor-α (TNF-α). These mediators promote atherogenesis and heart failure by inducing intimal infiltration and myocardial fibrotic remodeling[17]. Furthermore, the same inflammatory cytokines released from epicardial adipose tissue may contribute to the activation of hepatic stellate cells, thereby fostering liver fibrosis. Supporting a direct paracrine link, atherosclerotic plaques are detected more frequently in coronary arterial segments surrounded by this ectopic fat[18]. In their study of 147 patients with biopsy-proven MASLD, Liu et al[16] demonstrated that morphological and functional cardiac alterations were more pronounced in individuals with severe fibrosis. These data suggest that MASH and CVD may share synergistic mechanisms arising from a systemic pro-inflammatory, pro-atherogenic, and pro-fibrotic milieu sustained by ectopic adipose depots, although further investigation is required to confirm this hypothesis.
Systemic subclinical inflammation. In patients with MASLD, visceral adipose tissue secretes a profile of pro-inflammatory adipokines (TNF-α, IL-6, leptin) while simultaneously downregulating adiponectin production. This imbalance activates the NF-κB pathway in both the liver—promoting the transition from MASLD to MASH—and the endothelium, where it triggers dysfunction and accelerates atherothrombogenesis. MASLD induces a systemic inflammatory state through multiple complex interactions involving the gut microbiome, the liver, and adipose depots. MASH is characterized by inflammasome activation across various cell types, including both resident and infiltrating populations[19]. Furthermore, free fatty acids stimulate hepatocytes to secrete TNF-α, IL-6, and IL-8, thereby amplifying the systemic response[20]. Supporting this, Fricker et al[21] demonstrated that, in 2482 participants, the presence of hepatic steatosis was independently correlated with elevated serum concentrations of systemic inflammatory markers—including C-reactive protein, urinary isoprostanes, IL-6, intercellular adhesion molecule 1, and P-selectin—even after adjusting for BMI and other components of the metabolic syndrome. This low-grade systemic inflammation, considered secondary to the hepatic disorder, leads to the release of pro-inflammatory mediators that may foster atherosclerotic CVD by inducing endothelial dysfunction and enhancing plaque formation[22,23]. Consequently, it can be hypothesized that systemic inflammation constitutes the key mechanistic bridge linking MASLD to cardiovascular pathology.
Insulin resistance (IR) and hyperinsulinemia. IR is a central metabolic defect common to both MASLD and atherogenic dyslipidemia, even in normal weight individuals. Hyperinsulinemia stimulates hepatic lipid synthesis, enhances vascular smooth muscle cell proliferation, and reduces endothelial nitric oxide production. Impaired glucose metabolism and IR are critical drivers in the pathogenesis of both non-alcoholic fatty liver disease and CVD. Skeletal muscle IR diverts glucose away from glycogen synthesis within the muscle, shunting this substrate toward the liver[24]. The resulting increase in hepatic glucose delivery, coupled with hyperinsulinemia, activates sterol regulatory element-binding protein 1c, which upregulates key enzymes governing de novo lipogenesis. This cascade consequently elevates very-low-density lipoprotein production, promoting hypertriglyceridemia and MASLD[19]. Concurrently, hyperinsulinemia drives hepatic gluconeogenesis, further elevating circulating insulin levels and perpetuating a self-amplifying cycle of glucose dysregulation.
Oxidative stress and mitochondrial dysfunction. A shared pathological mechanism involves impaired fatty acid β-oxidation within the mitochondria of hepatocytes and cardiomyocytes, leading to the accumulation of reactive oxygen species (ROS), atherogenic modification of low-density lipoproteins (LDLs), and the initiation of cellular apoptosis. Koliaki et al[25] demonstrated that liver tissues from patients with MASLD exhibit mitochondrial dysfunction and elevated oxidant generation. These organelles regulate fat oxidation and energy production while also generating ROS via the electron transport chain. In obese individuals with IR, an early-stage increase in hepatic mitochondrial respiration occurs as an adaptive response; however, this compensatory mechanism dissipates with progression from MASLD to MASH. In obese patients with MASH, heightened hepatic oxidative stress—specifically H2O2—is observed due to diminished respiratory capacity, resulting in impaired insulin receptor signaling, oxidative DNA damage, and systemic inflammation, including elevated serum IL-6 levels[25]. Consequently, it can be hypothesized that supraphysiological oxidant levels promote IR[26].
It is well established that MASLD is associated with depleted hepatic glutathione (GSH), a phenomenon attributed to deficiencies in the nutrients required for its synthesis. This deficit, in turn, impairs the function of enzymes governing the GSH recycling pathway, thereby reducing the regeneration of its active form; a decline in hepatic enzyme activity consequently lowers the plasma concentration of GSH. These alterations ultimately compromise the overall antioxidant defense of the vascular wall, rendering the endothelium more susceptible to ROS-mediated injury. Under conditions of insufficient antioxidant protection due to low GSH levels, LDL oxidation is enhanced, accelerating endothelial damage and promoting atherogenesis.
Circulating GSH plays a pivotal role in protecting cells against oxidative stress, a condition inherent to hepatic steatosis that may contribute to cardiac and vascular injury. A decline in the ratio of reduced to oxidized GSH (GSSG; GSH/GSSG) serves as a sensitive biomarker of this redox imbalance. GSH deficiency heightens the risk of MASLD progression, as the depletion of antioxidant defenses potentiates further hepatocellular damage, inflammation, and fibrosis[27]. Bravi et al[28] demonstrated a significantly lower GSH/GSSG ratio in patients with type 2 diabetes and showed that insulin administration elevated this ratio, suggesting that the hormone may attenuate oxidative stress by modulating GSH redox status. As the liver is the principal site of GSH production, it plays a central role in the inter-organ homeostasis of this tripeptide and its precursor, cysteine[29,30]. Consequently, diminished hepatic synthesis may adversely affect the redox equilibrium in the heart and other distant organs. Clinical studies corroborate this, demonstrating that circulating GSH concentrations are reduced in patients with MASLD or MASH relative to healthy controls[31], and that lower plasma GSH levels are linked to heightened cardiovascular risk[32]. Therefore, impaired hepatic GSH synthesis in MASLD may instigate a systemic decline in antioxidant capacity, thereby exacerbating oxidative stress and representing a major risk factor for cardiovascular pathology. Furthermore, extracellular GSH can be recycled. Gamma-glutamyltransferase (GGT) is an enzyme that cleaves cysteine from circulating GSH to facilitate the replenishment of its intracellular pool. Elevated serum GGT activity reflects a systemic pro-oxidant state and is predictive of a higher incidence of both metabolic disorders and cardiovascular events[33].
Atherogenic dyslipidemia. The characteristic lipid triad—elevated triglycerides, decreased high-density lipoprotein (HDL) cholesterol, and increased small dense LDL particles—is observed independently of BMI and directly links MASLD to the risk of coronary atherosclerosis. Furthermore, this condition is an independent predictor of atherogenic dyslipidemia criteria and an elevated triglycerides/HDL ratio[34]. Mapouka et al[7] reported that lean patients exhibit mortality rates comparable to those of their obese counterparts (pOR = 1.4, 95%CI: 1.0-2.0, P = 0.06). This observation may be attributable to the pathogenetic drivers discussed above, namely oxidative stress and systemic inflammation, which serve as long-term mediators of extrahepatic complications.
The unifying factor, therefore, is the dysregulation of lipid and carbohydrate homeostasis in the setting of visceral obesity—a state clinically concealed by a normal BMI yet revealed by the presence of MASLD as an early sentinel of cardiometabolic risk. The designation "lean with disordered metabolism" applies to such individuals, in whom this hepatic phenotype represents less a primary liver disease than the hepatic manifestation of a systemic atherosclerotic process.
